Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium

doi:10.1016/S0046-8177(03)00425-8

Human Pathology

Volume 34, Issue 11, November 2003, Pages 1148-1154

https://doi.org/10.1016/S0046-8177(03)00425-8 Get rights and content

Abstract

PC-cell-derived growth factor (PCDGF, progranulin) is a novel autocrine growth factor that is overexpressed in human breast cancer cell lines. We have examined immunohistochemical PCDGF expression in 206 paraffin-embedded human breast lesions and investigated its association with clinicopathological variables. PCDGF staining was observed in breast carcinoma, whereas it was almost always negative in benign breast epithelium. PCDGF expression was more common in invasive ductal carcinoma (80% cases positive) than in invasive lobular carcinoma (53% positive). PCDGF staining was almost never observed in lobular carcinoma in situ. Ductal carcinoma in situ expressed PCDGF in 66% of the cases, and this expression correlated strongly with nuclear grade. Similar correlation was observed between PCDGF expression and histologic grade of invasive ductal carcinoma. Average Ki-67 index of PCDGF-negative/weakly positive invasive carcinomas (30.3) was significantly lower than that of strongly PCDGF-positive tumors (48.8, P = 0.01). A larger percentage of tumors that expressed PCDGF with a staining intensity of 2+ or 3+ were p53 positive (44%) than were PCDGF-negative tumors (25%), P = 0.02. PCDGF expression was independent of c-erbB-2 overexpression and of ER and PR status. Our study provides the first evidence of high incidence of PCDGF expression in human breast cancer in which it correlates with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics, as well as the virtual absence of expression in benign breast tissue, suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer.

Section snippets

Tissue samples

Two hundred six nonconsecutive archival formalin-fixed, paraffin-embedded human breast lesions from 152 patients were obtained from the University of Maryland Department of Pathology files and from the National Cancer Institute of Canada-Manitoba Breast Cancer Tumor Bank of the University of Manitoba, Winnipeg, Canada (kindly provided by Dr. Peter Watson). The 152 tissue blocks examined contained the following lesions: 27 ductal carcinoma in situ (DCIS), 12 lobular carcinoma in situ (LCIS), 124

PCDGF expression in human breast tissue and its association with histologic type

PCDGF expression was observed in 128 of 206 cases (62%; Table 2). Most benign breast epithelium was negative for PCDGF (25 of 26 cases, or 96%), as were most LCIS cases (11 of 12, or 92%). However, the majority of malignant noninvasive and invasive ductal lesions showed PCDGF expression. The difference in PCDGF expression between benign/LCIS and intraductal/invasive carcinomas was statistically significant (P = 0.001). Eighteen of the 27 DCIS (67%) and even a higher proportion of IDC, 99 of

Discussion

Our studies with human breast cancer cell lines have indicated the biological importance of PCDGF in breast cancer tumorigenesis,8, 9, 10 thereby warranting the investigation of its expression in archived pathological samples. This is the first report describing the expression of PCDGF in human breast tissue. We have shown that PCDGF is almost never expressed in benign breast epithelium. PCDGF expression was not seen in lobular carcinoma in situ, whereas the majority of invasive lobular

Acknowledgements

The authors thank Dr. Peter Watson, Ms. Michelle Parisien, and Linda Snell from the National Cancer Institute of Canada-Manitoba Breast Tumor Bank, funded by the National Cancer Institute of Canada (Winnipeg, Manitoba, Canada), for providing several of the IDC cases examined.

References (43)

J. Zhou et al.
Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line
J Biol Chem
(1993)
G.D. Plowman et al.
The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth
J Biol Chem
(1992)
S.Q. Xu et al.
The granulin/epithelin precursor abrogates the requirement for the insulin-like growth factor 1 receptor for growth in vitro
J Biol Chem
(1998)
L. Diaz-Cueto et al.
Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor)
Dev Biol
(2000)
R. Lu et al.
Stimulation of PC cell-derived growth factor (epithelin/granulin precursor) expression by estradiol in human breast cancer cells
Biochem Biophys Res Commun
(1999)
T. Beck et al.
Usefulness of immunohistochemical staining for p53 in the prognosis of breast carcinomasCorrelations with established prognosis parameters and with the proliferation marker, MIB-1
Gynecol Oncol
(1995)
J.A. van Dongen et al.
Ductal carcinoma in-situ of the breast; second EORTC consensus meeting
Eur J Cancer
(1992)
H. Zhang et al.
Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)
Proc Natl Acad Sci U S A
(1998)
V. Bhandari et al.
Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains
Proc Natl Acad Sci U S A
(1992)
Z. He et al.
Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo
Cancer Res
(1999)

R. Lu et al.

Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468

Proc Natl Acad Sci U S A

(2000)

R. Lu et al.

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Proc Natl Acad Sci U S A

(2001)

M.D. Linden et al.

Clinical application of morphologic and immunocytochemical assessments of cell proliferation

Am J Clin Pathol

(1992)

J.D. Jacquemier et al.

Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapyA multiparametric and immunohistochemical analysis

J Pathol

(1998)

J.S. Ross et al.

HER-2/neu (c-erb-B2) gene and protein in breast cancer

Am J Clin Pathol

(1999)

R. Molina et al.

p53 oncoprotein as a prognostic indicator in patients with breast cancer

Anticancer Res

(1998)

C.W. Elston et al.

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancerExperience from a large study with long-term follow-up

Histopathology

(1991)

J.S. Meyer et al.

Estrogen receptor assay of carcinomas of the breast by a simplified dextran-charcoal method

Am J Clin Pathol

(1978)

A. Norgren et al.

Improved method for assay of estradiol and progesterone receptors with special reference to breast cancer

Anticancer Res

(1982)

T. Yokota et al.

c-erbB-2, p53 protein expression and steroid hormone receptors in breast carcinomasAn immunohistochemical study

Anticancer Res

(1999)

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^☆: Supported in part by grants 9857-AFF and BCTR-2000-356 from the Susan G. Komen Breast Cancer Foundation, grants DAMD17-01-1-0551 from the Department of Defense (Frederick, MD) and grants CA 85367 from the National Institutes of Health (Bethesda, MD).

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Original contributionExpression of PC-cell-derived growth factor in benign and malignant human breast epithelium☆

Abstract

Section snippets

Tissue samples

PCDGF expression in human breast tissue and its association with histologic type

Discussion

Acknowledgements

J Biol Chem

J Biol Chem

J Biol Chem

Dev Biol

Biochem Biophys Res Commun

Gynecol Oncol

Eur J Cancer

Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)

Proc Natl Acad Sci U S A

Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains

Proc Natl Acad Sci U S A

Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo

Cancer Res

Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468

Proc Natl Acad Sci U S A

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor)

Proc Natl Acad Sci U S A

Clinical application of morphologic and immunocytochemical assessments of cell proliferation

Am J Clin Pathol

Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapyA multiparametric and immunohistochemical analysis

J Pathol

HER-2/neu (c-erb-B2) gene and protein in breast cancer

Am J Clin Pathol

p53 oncoprotein as a prognostic indicator in patients with breast cancer

Anticancer Res

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancerExperience from a large study with long-term follow-up

Histopathology

Estrogen receptor assay of carcinomas of the breast by a simplified dextran-charcoal method

Am J Clin Pathol

Improved method for assay of estradiol and progesterone receptors with special reference to breast cancer

Anticancer Res

c-erbB-2, p53 protein expression and steroid hormone receptors in breast carcinomasAn immunohistochemical study

Anticancer Res

Original contribution
Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium☆